Among the atopic diseases, asthma, hayfever and atopic dermatitis, the latter has the most pronounced immunological and pharmacological aberrancies. We have traced many of these abnormalities thrugh leukocyte studies and have recently been able to reproduce the defective cAMP responsiveness of atopic mononuclear leukocytes (MNL) by exposure of normal cells to inflammatory mediators (histamine and PGE1) and isoproterenol in culture. This model, in turn, led to our recent observation of abnormally high cAMP-phosphodiesterase (PDE) in the MNL of patients with active and latent atopic dermatitis. Kinetic studies of this phosphodiesterase indicates it to be a high Km, high Vmax type, distinct from normal mixed MNL enzyme but similar to that found in normal monocytes. Exposure of normal MNL to the above-mentioned agonists caused a shift in kinetics of that normal cAMP-PDE to activity levels resembling enzyme from atopic cells. We have postulated that in vivo exposure of leukocytes to elevated tissue histamine concentrations found in atopic dermatitis causes increased PDE activity and consequent decreased cAMP responsiveness. We intend to characterize the enzyme resulting from exposure of cells to histamine and to clarify the mechanism by which histamine causes the altered enzyme characteristics. We will compare these characteristics with enzyme from patients with atopic dermatitis and ascertain whether histamine or other mediators are responsible for the increased cyclic AMP-PDE activity or, alternatively, whether this increased activity is intrinsically atopic dermatitis and other atopic diseases. We also intend to evaluate the effects of various phosphodiesterase inhibitors on the high activity enzyme found in atopic dermatitis cells. We will evaluate various well-defined atopic disease groups to determine whether mononuclear leukocyte cAMP-PDE is a reliable biochemical marker for the atopic diathesis and for the level of disease activity. The proposed studies should help define the molecular abnormalities which characterize atopic dermatitis and allow us to focus more directly on correcting those abnormalities.